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1. Leveraging genomic diversity for discovery in an electronic health record linked biobank: the UCLA ATLAS Community Health Initiative

   https://doi.org/10.1186/s13073-022-01106-x  

   Johnson, Ruth; Ding, Yi; Venkateswaran, Vidhya; Bhattacharya, Arjun; Boulier, Kristin; Chiu, Alec; Knyazev, Sergey; Schwarz, Tommer; Freund, Malika; Zhan, Lingyu; et al (December 2022, Genome Medicine)

   Abstract Background Large medical centers in urban areas, like Los Angeles, care for a diverse patient population and offer the potential to study the interplay between genetic ancestry and social determinants of health. Here, we explore the implications of genetic ancestry within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative—an ancestrally diverse biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients ( N =36,736). Methods We quantify the extensive continental and subcontinental genetic diversity within the ATLAS data through principal component analysis, identity-by-descent, and genetic admixture. We assess the relationship between genetically inferred ancestry (GIA) and >1500 EHR-derived phenotypes (phecodes). Finally, we demonstrate the utility of genetic data linked with EHR to perform ancestry-specific and multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes. Results We identify 5 continental-scale GIA clusters including European American (EA), African American (AA), Hispanic Latino American (HL), South Asian American (SAA) and East Asian American (EAA) individuals and 7 subcontinental GIA clusters within the EAA GIA corresponding to Chinese American, Vietnamese American, and Japanese American individuals. Although we broadly find that self-identified race/ethnicity (SIRE) is highly correlated with GIA, we still observe marked differences between the two, emphasizing that the populations defined by these two criteria are not analogous. We find a total of 259 significant associations between continental GIA and phecodes even after accounting for individuals’ SIRE, demonstrating that for some phenotypes, GIA provides information not already captured by SIRE. GWAS identifies significant associations for liver disease in the 22q13.31 locus across the HL and EAA GIA groups (HL p -value=2.32×10 −16 , EAA p -value=6.73×10 −11 ). A subsequent PheWAS at the top SNP reveals significant associations with neurologic and neoplastic phenotypes specifically within the HL GIA group. Conclusions Overall, our results explore the interplay between SIRE and GIA within a disease context and underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping linked with EHR-based phenotyping. 

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2. Genome-wide association study of pancreatic fat: The Multiethnic Cohort Adiposity Phenotype Study

   https://doi.org/10.1371/journal.pone.0249615  

   Streicher, Samantha A.; Lim, Unhee; Park, S. Lani; Li, Yuqing; Sheng, Xin; Hom, Victor; Xia, Lucy; Pooler, Loreall; Shepherd, John; Loo, Lenora W.; et al (July 2021, PLOS ONE)

   Buchner, David A. (Ed.)

   Several studies have found associations between higher pancreatic fat content and adverse health outcomes, such as diabetes and the metabolic syndrome, but investigations into the genetic contributions to pancreatic fat are limited. This genome-wide association study, comprised of 804 participants with MRI-assessed pancreatic fat measurements, was conducted in the ethnically diverse Multiethnic Cohort-Adiposity Phenotype Study (MEC-APS). Two genetic variants reaching genome-wide significance, rs73449607 on chromosome 13q21.2 (Beta = -0.67, P = 4.50x10 -8 ) and rs7996760 on chromosome 6q14 (Beta = -0.90, P = 4.91x10 -8 ) were associated with percent pancreatic fat on the log scale. Rs73449607 was most common in the African American population (13%) and rs79967607 was most common in the European American population (6%). Rs73449607 was also associated with lower risk of type 2 diabetes (OR = 0.95, 95% CI = 0.89–1.00, P = 0.047) in the Population Architecture Genomics and Epidemiology (PAGE) Study and the DIAbetes Genetics Replication and Meta-analysis (DIAGRAM), which included substantial numbers of non-European ancestry participants (53,102 cases and 193,679 controls). Rs73449607 is located in an intergenic region between GSX1 and PLUTO , and rs79967607 is in intron 1 of EPM2A . PLUTO , a lncRNA , regulates transcription of an adjacent gene, PDX1 , that controls beta-cell function in the mature pancreas, and EPM2A encodes the protein laforin, which plays a critical role in regulating glycogen production. If validated, these variants may suggest a genetic component for pancreatic fat and a common etiologic link between pancreatic fat and type 2 diabetes. 

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3. From Basic to Humane Genomics Literacy: How Different Types of Genetics Curricula Could Influence Anti-Essentialist Understandings of Race

   Donovan, B.M.; Weindling, M.; Lee, D. (March 2021, Science and Education)

   Genetic essentialism of race is the belief that racial groups have different underlying genetic essences which cause them to differ physically, cognitively, or behaviorally. Apparently no published studies have explored if belief in genetic essentialism of race among adolescents differs after many weeks of formal instruction about different domains of genetics knowledge. Nor have any studies explored if such differences reflect a coherent change in students’ racial schemas. We use a quasi-experimental design (N = 254 students in 7th-12th grade) to explore these gaps. Over the course of three months, we compared students who learned from a curriculum on multifactorial inheritance and genetic ancestry to students who learned from their business as usual (BAU) genetics curriculum that discussed Mendelian and molecular genetics without any reference to race, multifactorial genetics, or genetic ancestry. Relative to the BAU condition, classrooms that learned from the multifactorial genetics and ancestry curriculum grew significantly more in their knowledge of multifactorial genetics and decreased significantly more in their genetic essentialist perceptions, attributions, and beliefs. From a conceptual change perspective, these findings suggest that classrooms using a curriculum emphasizing genetic complexity are more likely to shift toward a coherent anti-essentialist understanding of racial difference. 

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4. ClinVar and HGMD genomic variant classification accuracy has improved over time, as measured by implied disease burden

   https://doi.org/10.1186/s13073-023-01199-y  

   Sharo, Andrew G.; Zou, Yangyun; Adhikari, Aashish N.; Brenner, Steven E. (July 2023, Genome Medicine)

   Abstract BackgroundCurated databases of genetic variants assist clinicians and researchers in interpreting genetic variation. Yet, these databases contain some misclassified variants. It is unclear whether variant misclassification is abating as these databases rapidly grow and implement new guidelines. MethodsUsing archives of ClinVar and HGMD, we investigated how variant misclassification has changed over 6 years, across different ancestry groups. We considered inborn errors of metabolism (IEMs) screened in newborns as a model system because these disorders are often highly penetrant with neonatal phenotypes. We used samples from the 1000 Genomes Project (1KGP) to identify individuals with genotypes that were classified by the databases as pathogenic. Due to the rarity of IEMs, nearly all such classified pathogenic genotypes indicate likely variant misclassification in ClinVar or HGMD. ResultsWhile the false-positive rates of both ClinVar and HGMD have improved over time, HGMD variants currently imply two orders of magnitude more affected individuals in 1KGP than ClinVar variants. We observed that African ancestry individuals have a significantly increased chance of being incorrectly indicated to be affected by a screened IEM when HGMD variants are used. However, this bias affecting genomes of African ancestry was no longer significant once common variants were removed in accordance with recent variant classification guidelines. We discovered that ClinVar variants classified as Pathogenic or Likely Pathogenic are reclassified sixfold more often than DM or DM? variants in HGMD, which has likely resulted in ClinVar’s lower false-positive rate. ConclusionsConsidering misclassified variants that have since been reclassified reveals our increasing understanding of rare genetic variation. We found that variant classification guidelines and allele frequency databases comprising genetically diverse samples are important factors in reclassification. We also discovered that ClinVar variants common in European and South Asian individuals were more likely to be reclassified to a lower confidence category, perhaps due to an increased chance of these variants being classified by multiple submitters. We discuss features for variant classification databases that would support their continued improvement. 

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5. Assessing the contribution of rare genetic variants to phenotypes of chronic obstructive pulmonary disease using whole-genome sequence data

   https://doi.org/10.1093/hmg/ddac117  

   Kim, Wonji; Hecker, Julian; Barr, R Graham; Boerwinkle, Eric; Cade, Brian; Correa, Adolfo; Dupuis, Josée; Gharib, Sina A; Lange, Leslie; London, Stephanie J; et al (June 2022, Human Molecular Genetics)

   Abstract Rationale: Genetic variation has a substantial contribution to chronic obstructive pulmonary disease (COPD) and lung function measurements. Heritability estimates using genome-wide genotyping data can be biased if analyses do not appropriately account for the nonuniform distribution of genetic effects across the allele frequency and linkage disequilibrium (LD) spectrum. In addition, the contribution of rare variants has been unclear. Objectives: We sought to assess the heritability of COPD and lung function using whole-genome sequence data from the Trans-Omics for Precision Medicine program. Methods: Using the genome-based restricted maximum likelihood method, we partitioned the genome into bins based on minor allele frequency and LD scores and estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio in 11 051 European ancestry and 5853 African-American participants. Measurements and Main Results: In European ancestry participants, the estimated heritability of COPD, FEV1% predicted and FEV1/FVC ratio were 35.5%, 55.6% and 32.5%, of which 18.8%, 19.7%, 17.8% were from common variants, and 16.6%, 35.8%, and 14.6% were from rare variants. These estimates had wide confidence intervals, with common variants and some sets of rare variants showing a statistically significant contribution (P-value < 0.05). In African-Americans, common variant heritability was similar to European ancestry participants, but lower sample size precluded calculation of rare variant heritability. Conclusions: Our study provides updated and unbiased estimates of heritability for COPD and lung function, and suggests an important contribution of rare variants. Larger studies of more diverse ancestry will improve accuracy of these estimates. 

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